Targeted disruption ofBcl-2af3 inmice.: Occurrence ofgrayhair, polycystic kidney disease, andlymphocytopenia

Micecarrying ablated coding regions ofthe bd-2aandbd-2P transcripts havebeenmade.bl-2--mu- tants aresmaller butviable, although about half ofthemdieby 6weeksofage.Asshownearlier withsomatic bcl-2 gene- targeted mice, thenumber oflymphocytes mark decreased within fewweeks after birth while other hematopoietic lineages remained unaffected. Amonglymphocytes, CD8+Tcells dis- appeared mostquickly followed byCD4+Tcells, whereas B cells wereleast affected. bcl-2-1- lymphocytes, however, could respond normally tovarious stimuli including antl-CD3, Con A,phorbol 12-myriste 13-acetate plus lonomycin, interleukin 2,lipopolysaccharide, andanti-IgM antibody. Abnormalities amongnonlymphold organs include smaller auricles, hair color turning grayat4-5weeksofage,andpolycystic kidney diseas-like change ofrenal tubules. These results suggest that Bd-2maybeinvolved durinmorphogenesis where Inductive interactions between epithelium andmesenchyme areimpor- tant suchasinthekidneys, hair follicles, andperichondrium ofauricles. Surprigly, thenervous system, intestines, and skin appear normal despite thefact that these organs showhigh levels ofendogeneous Bcl-2 expression innormal mice. bcl-2 isaprotooncogene initially found atthebreakpoint of thet(14;18) chromosomal translocation associated inover 60%ofhumanfollicular lymphomas (1-3). Thetranslocation juxtaposes thebcl-2 genewiththeimmunoglobulin heavy- chain gene, resulting intheformation ofbcl-2-immunoglob- ulin heavy-chain fusion gene(4-6). Thederegulation ofBcl-2 maypromote cell survival bypreventing programmed cell death inmany,butnotall, types ofcells (7-13). Endogenous Bc1-2 isnormally expressed inmature TandBlymphocytes andinother long-lived cells suchasneurons, stemcells in intestine andskin, immature progenitors oferythrocytes, myelocytes, thrombocytes, andhormonally regulated glan- dular epithelium (14). Specifically, fetal tissue studies suggest that Bc1-2 maybeinvolved inkidney andhair follicle mor- phogenesis (15). Cells derived fromtransgenic micebearing deregulated/overexpressed